Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy

Cashman, Timothy J.; Josowitz, Rebecca; Johnson, Bryce V.; Gelb, Bruce D.; Costa, Kevin D.

doi:10.1371/journal.pone.0146697

Cited by 77 publications

(60 citation statements)

References 43 publications

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“…On the other hand, in all cases, the PS-only conditions decreased VW compared to control, thus minimizing arrhythmogenic risk in an hMSC dose-dependent manner. Spontaneous beat rate variability measurements in hECTs—a proposed surrogate of arrhythmogenicity 40,41 —with low-level hMSC HC and PS interventions qualitatively support these trends (Online Figure VIII). …”

Section: Resultsmentioning

confidence: 70%

“…21 Furthermore, our model trends are consistent with our original hECT data on spontaneous beat rate variability—a proposed surrogate of arrhythmogenicity. 40,41 Most importantly, VW analyses predicted that hMSC supplementation (involving hMSC PS+HC mechanisms) did not adversely impact arrhythmogenesis, and may even be anti-arrhythmogenic under some conditions; such findings may help explain why hMSCs are mainly reported to have either no effect, 14 or favorable protective effects, 13 on arrhythmogenesis in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

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Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

Mayourian

Cashman

Ceholski

et al. 2017

Circulation Research

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Rationale Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved. Objective To better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. Methods and Results Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/SERCA activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased approximately 4-fold compared to non-hMSC-supplemented controls during physiologic 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential pro-arrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosomes-enriched, but not exosomes-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT developed force and expression of calcium handling genes (e.g., SERCA2a, L-type calcium channel). Conclusions Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility.

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Section: Resultsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

Mayourian

Cashman

Ceholski

et al. 2017

Circulation Research

Self Cite

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“…An image is also provided showing a longitudinal section of an hECT stained with hematoxylin and eosin after 12 days in culture (bottom). Reprinted with permission (Cashman et al, 2016). D .…”

Section: Figurementioning

confidence: 99%

Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening

Smith

Macadangdang

Leung

et al. 2017

Biotechnology Advances

123

102

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Improved methodologies for modeling cardiac disease phenotypes and accurately screening the efficacy and toxicity of potential therapeutic compounds are actively being sought to advance drug development and improve disease modeling capabilities. To that end, much recent effort has been devoted to the development of novel engineered biomimetic cardiac tissue platforms that accurately recapitulate the structure and function of the human myocardium. Within the field of cardiac engineering, induced pluripotent stem cells (iPSCs) are an exciting tool that offer the potential to advance the current state of the art, as they are derived from somatic cells, enabling the development of personalized medical strategies and patient specific disease models. Here we review different aspects of iPSC-based cardiac engineering technologies. We highlight methods for producing iPSC-derived cardiomyocytes (iPSC-CMs) and discuss their application to compound efficacy/toxicity screening and in vitro modeling of prevalent cardiac diseases. Special attention is paid to the application of micro- and nano-engineering techniques for the development of novel iPSC-CM based platforms and their potential to advance current preclinical screening modalities.

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“…(56) Human engineered cardiac tissues from a patient with a BRAF mutation recapitulated the HCM phenotype, providing a cell culture approach to study disease mechanisms and therapies in vitro . (57) Genome editing capabilities have also generated specific interest as a mechanism to correct a mutant allele encoding a structural component of the sarcomere in isolated non-syndromic cardiomyopathy. In a mouse model of HCM, adenoviral constructs were used to silence the mutant allele but not the wild-type allele, ameliorating the disease phenotype.…”

Section: Toward Novel Disease-specific Therapeuticsmentioning

confidence: 99%

Genetics of paediatric cardiomyopathies

Ware

2017

Current Opinion in Pediatrics

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Purpose of review Pediatric cardiomyopathy is a rare disease with a genetic basis. The purpose of this review is to discuss the current status of genetic findings in the pediatric cardiomyopathy population and present recent progress in utilizing this information for management and therapy. Recent findings With increased clinical genetic testing, an understanding of the genetic causes of cardiomyopathy is improving and novel causes are identified. Recent progress in identifying the scope of genetic variation in large population datasets has led to reassessment and refinement of our understanding of the significance of rare genetic variation. As a result, the stringency of variant interpretation has increased, at times leading to revision of previous mutation results. Transcriptome and epigenome studies are elucidating important pathways for disease progression and highlight similarities and differences from adult cardiomyopathy. Therapy targeted toward the underlying cause of cardiomyopathy is emerging for a number of rare syndromes such as Pompe and Noonan syndromes, and genome editing and induced pluripotent stem cells provide promise for additional precision medicine approaches. Summary Genetics is moving at a rapid pace in pediatric cardiomyopathy. Genetic testing is increasingly being incorporated into clinical care. While challenges in interpretation of rare genetic variation remains challenging, the opportunity to provide management and therapy targeted toward the underlying genetic cause is beginning to be realized.

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Human Engineered Cardiac Tissues Created Using Induced Pluripotent Stem Cells Reveal Functional Characteristics of BRAF-Mediated Hypertrophic Cardiomyopathy

Cited by 77 publications

References 43 publications

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity

Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening

Genetics of paediatric cardiomyopathies

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